In 2013, there were an estimated 44.4 million people with dementia worldwide. According to Alzheimer’s Disease International, this number will increase to an estimated 135.5 million by 2050. Research at Southampton is tackling dementia by analysing the lifecourse of the illness to develop new and improved treatments.
About dementia
Dementia is one of the biggest health challenges of our time; in the UK alone it affects around 800,000 people, but as well as taking a huge personal toll, it is estimated that the societal cost of dementia in the UK in 2012 was £23bn.
The term ‘dementia’ refers to a range of illnesses – of which Alzheimer’s disease is the most common – that cause a gradual decline in brain function. “The biggest risk factor for developing Alzheimer’s disease is age,” says Dr Mariana Vargas Caballero from the Institute for Life Sciences, at the University. “And the risk of getting Alzheimer’s for people over 85 is one in six,” she adds. Alzheimer’s gene
Dr Cheryl Hawkes, Senior Research Fellow in Medicine at Southampton explains that in order to tackle Alzheimer’s more needs to be done to identify people who might be at risk of developing the disease. Her research investigates apolipoprotein-E (APO-E), a class of proteins that appear consistently in genome-wide association studies of Alzheimer’s. “APO-E carries cholesterol around in our body. If you have two copies of the APO-E4 allele in your genome, you have a 12-fold higher risk of developing Alzheimer’s and at an earlier age,” says Cheryl.
While Cheryl investigates how APO-E increases the risk of Alzheimer’s disease, Mariana and her team investigate synaptic mechanisms in the brain, and look at how the building blocks of plaques and tangles, amyloid-beta and tau proteins, build up and affect neuronal connections leading to memory loss, one of the symptoms of Alzheimer’s. “We know that someone who is going to get Alzheimer’s has a long window of time, as much as 10-15 years, of changes in their brain, before they have any symptoms such as memory loss,” she says. “We hope to find out how the disease starts and clarify some of the drug targets, so that in time new treatments can be developed,” she adds.
Although a diagnosis of Alzheimer’s disease can be devastating, people with the illness can be supported to manage their symptoms and live an active and enjoyable life for some time before the effects become severe
However, clinicians and carers have often noticed that when a person with Alzheimer’s becomes ill with a secondary infection or disease their cognitive abilities go into a rapid decline, and symptoms such as depression and anxiety worsen.
Improving quality of life
Work by Hugh Perry, Professor of Experimental Neuropathology, and his colleagues at the University has generated new insights into the biological basis of the phenomenon, knowledge that could be used to modify the symptoms of Alzheimer’s and make a real difference to the quality of life of people with the illness. Inflammation is one aspect of the immune system that protects our body from infection and injury. It is activated by specialist immune cells, known as macrophages that are present in all the body’s tissues. The macrophages act as a first line of defence by killing pathogens, such as viruses or bacteria, and promoting the repair of injured tissue.
The inflammation that plays a role in Alzheimer’s disease is associated with the macrophages of the brain, known as microglia. Previous research has shown that people with Alzheimer’s disease have more microglia in their brains than healthy people and that these cells are ‘primed’ or partially activated by the ongoing degeneration of neurons.
“When you get a disease or infection, you know about it because molecules released by immune cells communicate with the brain and you feel ill,” says Hugh. “You might become feverish, want to stay in bed and sleep or lose your appetite, for example. Although unpleasant, these symptoms, known as ‘sickness behaviours’, are a beneficial outcome of the body’s communication with the brain because they cause us to adopt behaviours that will help us fight off the illness.”
This communication process involves the microglia, which in healthy brains are kept under tight control. However, in the brain of a person with Alzheimer’s disease this communication process causes the primed microglia to become overactive and damage healthy brain cells, speeding up the progress of dementia
Identifying molecular markers Hugh and his team identified a number of molecular markers that are normally carefully balanced in immune cells, and observed their behaviour in microglia affected by neurodegeneration as well as microglia affected by neurodegeneration and inflammation. By doing so, they were able to understand the mechanism that caused the microglia to produce damaging inflammatory molecules.
“These signalling pathways to the brain are part of the complex mechanism of homeostasis, through which the body keeps itself in a state of equilibrium,” comments Hugh. “It is only in relatively recent history that humans have lived long enough to develop degenerative brain diseases, so evolution hasn’t caught up and found a way to protect us from this maladaptive response to the signalling process. Instead of being beneficial, in people with dementia the process has become damaging.”
To build on the findings of preclinical experiments, Hugh teamed up with Clive Holmes, Professor of Biological Psychiatry at the University. Funded by the Alzheimer’s Society, Clive and his research team recruited a cohort of about 300 people with Alzheimer’s disease and monitored them over six months. The study looked at how their cognitive abilities changed as well as variations in their symptoms of sickness behaviour, such as depression, anxiety and apathy. This information was then related to whether they had had any infections during that six-month period.
The study found that people who had systemic inflammation – likely to be caused by secondary illnesses (comorbidities) common in older people – and an infection during the six-month period declined much more rapidly than those who didn’t, showing a clear association between infection and the progression of Alzheimer’s disease. It also showed that some sickness behaviours, such as apathy, depression and anxiety, were more frequent for people with infections and systemic inflammation.
Hugh says: “Given our understanding of the mechanisms by which systemic inflammation communicates with the brain, we propose that comorbidities drive the progression of Alzheimer’s disease. This could also be true for other neurodegenerative diseases.”
Broad applications
The University has been at the forefront of this area of research for many years, and while Alzheimer’s disease has been the focus of recent studies, the work has implications for many fields of human neurodegenerative disease and has attracted wide interest.
“The principles that underpin our findings are generic,” says Hugh. “For example, there are researchers worldwide looking at the role of systemic inflammation in driving other diseases such as multiple sclerosis.”
Related projects at Southampton are also ongoing. For example, Dr Jessica Teeling, Lecturer in Immunology, has teamed up with colleagues in ophthalmology to see if there is a link between inflammation and eye disease. Dr Tracy Newman, Lecturer in Clinical Neurosciences at Southampton, is working with colleagues at the University’s Institute of Sound and Vibration Research to see whether systemic disease impacts on people with hearing problems.
“Achieving these kinds of innovations involves crossing boundaries and sharing ideas between basic scientists, clinicians, immunologists, psychologists, neurochemists and others.” From risk factors such as APO-E, investigating how amyloid-beta and tau proteins build-up affects memory loss, to understanding how other illnesses can cause deterioration in patients; Southampton researchers are tackling the lifecourse of Alzheimer’s disease. “If we can start treating people early enough, and help people age in a healthier way, there is the potential to stem the growth of the disease,” says Cheryl. “The aim is also to be able to identify a way in which amyloid-beta can be removed from the brain, so that the disease can be reversed.”
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